Classifications

• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B40/00—Libraries per se, e.g. arrays, mixtures
  • C40B40/04—Libraries containing only organic compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
  • C07C291/10—Isocyanides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/78—Ring systems having three or more relevant rings
  • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
  • C07D311/82—Xanthenes
  • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
  • C07D311/88—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F8/00—Chemical modification by after-treatment
  • C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B20/00—Methods specially adapted for identifying library members
  • C40B20/04—Identifying library members by means of a tag, label, or other readable or detectable entity associated with the library members, e.g. decoding processes
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B30/00—Methods of screening libraries
  • C40B30/04—Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
  • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/11—Compounds covalently bound to a solid support

Definitions

• the present invention relates to polymer supports useful in solution and solid-phase synthesis. It relates more specifically to functionalized polymeric reagents, comprising an acid labile isonitrile moiety. In further aspects the present invention also relates to use of such functionalized polymeric reagents in solution and solid-phase synthesis, a method for preparing an organic compound by solution or solid-phase synthesis using such functionalized polymeric reagents, a method for preparing such functionalized polymeric reagents and to kits comprising the functionalized polymeric reagenta according to the invention. The present invention also relates to new intermediates for use in the preparation of the novel functionalized polymeric reagents.
• solid-phase synthesis has received a lot of attention lately.
• the reason for this is that solid-phase synthesis has several advantages compared to traditional solution-phase synthesis. Examples of such advantages include the ease with which products can be separated and purified from excess reagents by a simple washing step and the rapid isolation of product when cleaved and washed from the polymeric support.
• a prerequisite for solid-phase synthesis is a functionalized and stable polymeric support.
• Many of the commercially available polymeric supports have been developed for solid- phase peptide synthesis and are therefore not inevitably suitable for solid-phase synthesis of compounds with non-peptidic structures.
• solid-phase synthesis exhibits several shortcomings due to the nature of heterogeneous reaction conditions, of which non-linear kinetic behavior is one.
• insoluble polymers such as cross-linked polystyrene
• soluble polymers such as PEG
• One alternative is to use multicomponent reactions involving at least 3 reactants, which directly gives the product in a very efficient process.
• MCR multicomponent reactions
• Ugi MCR multicomponent reactions
• Multicomponent reactions can be performed either in solution or on solid phase.
• the solution phase alternative has proven its efficiency for the synthesis of a large number of biological compound, its major drawback is the need of purification steps in order to remove the excess of starting materials. This slows down the overall production process and/or limits its appropriateness for automated or semi-automated synthesis.
• One commercially available functionalized polymeric reagent comprising an isonitrile moiety is shown below in Figure 1.
• the isonitrile moiety can not be cleaved from the polymeric support by acid treatment.
• the present invention overcomes a novel use for functionalized polymeric reagents comprisingan isonitrile moiety.
• Isonitriles have always been a poor source of diversity in combinatorial chemistry. This is due to the low number of commercially available isonitriles and the cost associated with time-consuming efforts of custom syntheses of a large number of diverse isonitriles.
• the present invention overcomes these problems by use of a resin capture strategy where the reactive isonitrile moiety is attached to the polymeric support in such a way as to make it cleavable by acid.
• the resin capture strategy used has a further advantage in that it gives no by-products that are fragments of the desired final product. Compounds synthesized by this resin capture strategy and released by acid cleavage are pure and do not require any further purification steps.
• the present invention provides a functionalized polymeric reagent comprising a linker moiety for use in solution and solid-phase synthesis.
• the linker is compatible with a number of reagents and reaction conditions used in the synthesis of organic compounds.
• the functionalized polymeric reagent is also useful in combinatorial chemistry.
• one aspect of the present invention is a functionalized polymeric reagent for use in solution and solid-phase synthesis.
• the functionalized polymeric reagent comprises a linker, and said linker comprises an acid labile isonitrile moiety.
• the linker is covalently attached to the polymeric support.
• the present invention provides a method for preparing an organic compound by solution or solid-phase synthesis.
• the method comprises the step of immobilizing a substrate compound on the polymeric support via said isonitrile moiety.
• the thereby attached substrate compound is thereafter taken through at least one further organic reaction step to produce the desired compound, which is thereafter cleaved from the polymeric support and isolated.
• said method is performed with a variegated population of substrates and/or a plurality of organic reactions to provide a library of organic compounds.
• the present invention provides a method for preparing an organic compound by solution or solid-phase synthesis.
• the method comprises the step of a multi- component reaction being performed on the acid labile isonitril moiety of the functionalized polymeric reagent.
• the multi-component reaction is an Ugi or an Ugi-type reaction.
• the present invention provides a method for preparing a functionalized polymeric reagent.
• the method comprises the step of reacting a suitable polymeric support comprising an amino group with a "formylating" reagent.
• the thereby produced formamido group is thereafter converted to an isonitrile moiety.
• the amino group is treated with 2,4,5-trichlorophenylformate in DMF and the resulting formamido group is treated with triphenylphosphine / carbon tetrachloride and triethylamine in dichloromethane.
• the present invention provides new intermediates for use in the preparation of the novel functionalized polymeric reagents. Accordingly, it is an object of the present invention to provide a functionalized polymeric reagent for use in solution or solid-phase synthesis.
• the present invention relates to functionalized polymeric reagents suitable for solution and solid-phase synthesis, to preparation of said functionalized polymeric reagents, and to use of said functionalized polymeric reagents in solution and solid-phase synthesis of organic compounds, including libraries.
• the present invention provides a functionalized polymeric reagent for use in solution and solid-phase synthesis.
• the functionalized polymeric reagent comprises a polymeric support and an acid labile isonitrile moiety , wherein said polymeric support comprises a polymer and a linker.
• the linker is covalently attached to the polymer and the isonitrile moiety is covalently attached to the linker.
• Preferred functionalized polymeric reagents of the present invention are those of Formula I
• X is oxygen, a PEG-chain or a -(CH2) n -CONH- group
• R is carbon, hydrogen, phenyl, or substituted phenyl group
• R " is hydrogen, phenyl, or substituted phenyl group
• R is hydrogen, Ci-C ⁇ alkyl, Cj-Cg alkoxy, or phenoxy,
• R is hydrogen, Cj-Cg alkyl, C ⁇ -C alkoxy, or phenoxy, and n is an integer from 1 to 4.
• More preferred functionalized polymeric reagents of the present invention are
• R is a polymer directly attached to the linker or through a PEG-chain or a - (CH 2 ) n -CONH- group.
• functionalized polymeric reagent denotes a reagent that is covalently attached to a linker moiety, and said linker is covalently attached to a polymer.
• polymeric support denotes a polymer covalently attached to a linker moiety, which can optionally further be attached to a substrate compound.
• linker denotes a reactive functional group that can be used to link molecules onto polymeric supports.
• acid labile isonitrile denotes an isonitrile moiety which is cleaved from the linker when treated with aqueous trifluoroacetic acid (95%) at room temperature with a half time of less than 30 minutes.
• substrate compound denotes a compound to be modified in a subsequent reaction step.
• immobilize denotes the act of linking, e.g. a substrate compound, by means of chemical or biological procedure to a polymeric support.
• multicomponent reaction denotes a one-pot reaction that form products from at least three different starting materials and incorporate substantial portions of these reagents into the product. This includes reactions involving at lest three different functional groups, some of which may be parts of the same reagent molecule.
• variable population denotes a population including at least two different chemical entities, e.g., of different chemical structure.
• a “variegated population” of nucleophiles would comprise at least two different nucleophiles.
• substituted phenyl denotes a phenyl group substituted with at least one of the following; C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, halogen, or phenoxy group.
• Formylating reagent denotes a reagent that can convert an amino group into a formamido group.
• Suitable soluble and insoluble polymers therefore consists of those known to the skilled artisan in the art of solution or solid-phase synthesis.
• suitable insoluble polymer include, but is not limited to, inorganic substrates, e.g. kieselguhr, silica gel and controlled pore glass, and polymeric organic substrates, e.g. polystyrene, polypropylene, polyethylene glycol, , as well as composite inorganic/polymeric substrates such as polyacrylamide supported within a matrix of kieselguhr particles.
• Preferred insoluble polymers are 1 % DVB polystyrene and polystyrene-PEG.
• suitable soluble polymers include, but is not limited to, polystyrene (not cross-linked, polyvinyl alcohol, polyethylene imine, polyacrylic acid, polymethylene oxide, PEG, polypropylene oxide, cellulose, polyacrylamide, PEG with 3,5- diisocyanatobenzyl chloride. PEG with 3-nitro-3-azapentane 1,5-diisocyanate, polyvinyl alcohol-poly( 1 -vinyl-2-pyrrolidinone, polystyrene-poly(vinyl-substituted monosaccharides), poly(N-isopropylacrylamide)-poly(acrylic acid derivatives).
• polystyrene not cross-linked, polyvinyl alcohol, polyethylene imine, polyacrylic acid, polymethylene oxide, PEG, polypropylene oxide, cellulose, polyacrylamide, PEG with 3,5- diisocyanatobenzyl chloride.
• linker is not limited to MAMP resin (amino-(4-methoxyphenyl)methyl polystyrene) (A), and therefore also includes, but is not limited to, Rink amide (B), Wang amino (C), Sasrin amino (D), Sieber amide (E) and 2-chlorotrityl linker (F) shown in Figure 2 below.
• R represents the polymeric support either directly attached to the linker or through a spacer moiety, such as a PEG-chain or a -(CH2) n -CONH- group.
• the functionalized resin is prepared by mixing a polymeric support (for example, amino MAMP linker 100-200 mesh or 200-400 mesh, commercially available from Novabiochem) in a polar solvent (e.g., DMF) with a suitable "formylating" reagent, e.g. 2,4,5-trichlorophenylformate, as shown in figure 3.
• a polymeric support for example, amino MAMP linker 100-200 mesh or 200-400 mesh, commercially available from Novabiochem
• a polar solvent e.g., DMF
• suitable "formylating" reagent e.g. 2,4,5-trichlorophenylformate
• the formed formamido intermediate is thereafter reacted at room temperature with carbon tetrachloride (CCI4) / triphenylphosphine (PPh3) in a non-polar solvent, e.g. dichloromethane (DCM) for approximately 3 hours in the presence of a base, e.g. triethylamine (Et ⁇ N) to give the corresponding isonitrile.
• CCI4 carbon tetrachloride
• Ph3 triphenylphosphine
• a non-polar solvent e.g. dichloromethane (DCM)
• a base e.g. triethylamine (Et ⁇ N)
• reaction with the functionalized polymeric reagent or polymeric support can be assessed according to standard techniques such as microanalysis, spectroscopic analysis, or by colorimetric tests. For example, the formation of an isonitril moiety can be monitored by Fourier-transform infra-red spectroscopy (FT-IR), e.g., by monitoring the isonitril stretch at 2138 cm .
• FT-IR Fourier-transform infra-red spectroscopy
• the resin is preferably purified by washing. To ensure removal of excess reagents, several cycles of washing, preferably with solvents of a variety of polarities, can be carried out.
• the functionalized polymeric reagent or polymeric support has been prepared and washed it is stable at room temperature for long periods of time.
• the functionalized polymeric reagent can be stored for extended periods of time without loss of activity.
• the present invention provides a functionalized polymeric reagent, comprising an acid labile isonitrile moiety for use in solution and solid-phase synthesis.
• Compounds can be cleaved from the polymeric support with a variety of acids including, but not limited, to the following; TFA in DCM (20%). 4 M HC1 in dioxane, HF, acetic acid in DCM (80%).
• TFA in DCM
• 4 M HC1 in dioxane, HF, acetic acid in DCM 80%.
• a person skilled in the art can easily optimize the conditions to get the best possible result in the cleavage step.
• the resin-bound compounds are preswollen in DCM for 10 min, the resin filtered and a solution of DCM:TFA:water (80: 18:2) or 4M HC1 in Dioxane was added and the reaction mixture was agitated for 1 hour at room temperature. The solution is filtered and evaporated to give the crude final compound.
• the present invention provides a method for synthesizing organic compounds by solution or solid-phase synthesis.
• the method includes the steps of immobilizing a substrate compound on a polymeric support and at a later stage, cleaving the product from the polymeric support with an acid.
• the substrate compound is provided as a variegated population of substrate compounds, such that a library of organic compounds can be prepared.
• the immobilized substrate compound can be chemically manipulated while attached to the polymeric support.
• the method for synthesizing organic compounds by solution or solid-phase synthesis can include a plurality of further reaction steps, after the immobilizing step but before the cleaving step.
• Such synthetic manipulations include reactions, which are standard in solution and solid-phase synthesis.
• the reaction conditions for such manipulations will generally be selected to avoid cleavage of the substrate compound from the support, unless such concomitant cleavage is desired.
• the invention provides a method for the solution or solid-phase supported chemical synthesis of libraries.
• the method comprises the step of reacting a substrate compound, which is immobilized on a polymeric support of the invention, with reagent molecules under conditions such that a library of compounds is prepared.
• a library of compounds is prepared.
• at least one of the substrate compound or the reagent molecule is provided as a variegated population thereof.
• the method can include the step of cleaving the library of compounds from the polymeric support. Such a cleavage step can be concomitant with the reacting step, or. in certain embodiments, can be a separate cleavage step.
• Combinatorial libraries can be screened to determine whether any members of the library have a desired activity, and. if so, to identify the active compounds.
• Soluble compound libraries can be screened by affinity chromatography with an appropriate receptor to isolate ligands for the receptor, followed by identification of the isolated ligands by conventional techniques (e.g., mass spectrometry, NMR, and the like).
• Contacting the compounds with a soluble receptor can screen immobilized compounds; preferably, the soluble receptor is conjugated to a label (e.g., fluorophores, calorimetric enzymes, radioisotopes, luminescent compounds, and the like) that can be detected to indicate ligand binding.
• immobilized compounds can be selectively released and allowed to diffuse through a membrane to interact with a receptor.
• Combinatorial libraries of compounds can also be synthesized with "tags" to encode the identity of each member of the library.
• this method features the use of inert, but readily detectable, tags that are attached to the solid support or to the compounds.
• tags When an active compound is detected (e.g., by one of the techniques described above), the identity of the compound is determined by identification of the unique accompanying tag.
• This tagging method permits the synthesis of large libraries of compounds that can be identified at very low levels.
• a variegated population of substrate compounds can provide diversity in a combinatorial synthesis.
• Several methodologies have been developed to perform combinatorial chemistry. Examples of such methodologies include, but is not limited to, the mix and split technology and IRORI MiniKans.
• the polymeric support of the invention is suitable for use with multicomponent reactions, but not limited to them.
• Multicomponent reactions have become increasing common and have been extensively reviewed see e.g. Lutz Weber, Synlett 1999, no 3, 366-374: Kevin Short, Tetrahedron vol.53. no!9, 6653-6679, 1997: Sang Kim, Tetrahedron Letters, 39 (1998) 6993-6996; Blacburn, Tetrahedron Letters (1998) 39, 5469-5472, Bienayme , Angew. Chem. Int. Ed. (1998) 37. no 16; Blackburn 39, (1998) 3635-3638 Tetrahedron Letters.
• a multicomponent reaction is sequences of bimolecular reaction steps that proceed according to the zipper principle, i.e. each reaction step is a prerequisite for the following step.
• multicomponent reactions include but are not limited to, ⁇ -aminoalkylation (Mannich), Passierini, Ugi and Ugi-type.
• Ugi and Ugi-type reactions are preferred multicomponent reactions to be used with the polymeric supports of the present invention.
• Ugi and Ugi-type reactions give access to compounds and functionalities of great interest for a medicinal chemist, e.g. heterocyclic compounds.
• the invention provides methods for the multicomponent synthesis of organic compounds.
• the method comprises the step of reacting the isonitrile moiety with at least two reagent molecules simultaneously under conditions such that a multicomponent reaction is achieved.
• the preferred embodiment shown in Figure 4 is advantageous since it allows a multicomponent reaction to be performed directly onto the acid labile isonitrile moiety of the functionalized polymeric reagent.
• the example outlined above consists of a multicomponent Ugi-type condensation wherein the isonitrile moiety of the functionalized polymeric reagent is reacted with 2 different source of diversity, aldehydes and heteroaromatic amidines.
• This Ugi-type reaction leads efficiently and in a one step process to the fused 3-aminoimidazoles, using the resin capture strategy.
• the final compounds are of high purity after acid cleavage.
• 3-aminoimidazoles has been synthesized according to the present invention.
• a wide range of aldehydes and heteroaromatic amidines was utilised to test the functionalized polymeric reagent and showed the efficiency of the resin capture by obtaining a high yield and excellent purity of the final products.
• Typical procedure for the synthesis of fused 3- aminoimidazoles by Ugi type reaction and resin capture strategy is described in Example 3, below.
• the fused 3-aminoimidazoles contains a nitrogen atom, involved in an amine bond with the polymeric support, which can be further reacted with various electrophilic molecules, e.g. acyl halides, alkyl halides, or sulfonyl halides, and thereafter, be cleaved from the polymeric support.
• This tandem reaction process increases the diversity which can be introduced onto the 3-fused aminoimidazole core.
• the thereby introduced additional diversity is a further advantage of the present invention, since the access of these compounds by traditional solution-phase without polymeric support is cumbersome, since the corresponding isonitriles are either not commercially available or time-consuming to synthesize. Due to the low number of commercially available isonitriles able to be utilised in combinatorial chemistry ( ⁇ 20) and the cost and time-consumption of custom syntheses, the isonitriles have always been the poorest source of diversity involves in the Ugi reaction.
• the amino functionality of the aminoimidazoles can be utilised for further reactions, such as acylation or alkylation reactions.
• acyl chlorides, sulfonyl chlorides or alkyl halides can be used as source of diversity and will enhance the diversity of the aminoimidazoles.
• the Tandem reaction concept by coupling a multi component reaction with an additional alkylation or acylation step makes the whole process highly efficient with respect to the final diversity of the aminoimidazoles synthesized.
• the present invention also have a postitive impact on the size and the speed by which a library can be generated.
• tandem 3CC+1 strategy has enhanced the diversity of the fused 3- aminoimidazoles by using 3 non-exhaustive sources of diversity, i.e. acyl chlorides, alkyl halides and sulfonyl chlorides.
• 3 non-exhaustive sources of diversity i.e. acyl chlorides, alkyl halides and sulfonyl chlorides.
• the typical procedures for the synthesis of these compounds are described below in Example 3.
• the polymeric support of the present invention can also be used in general organic chemistry manipulations, such as cycloaddition reactions, as a dehydrating agent or as a scavenger, e.g. for the removal of alkyl halides, phosphines, acid chlorides, aldehydes and ketones.
• the present invention also provides a kit for use in solution and solid-phase synthesis.
• the kit includes a functionalized polymeric reagent of the present invention, i.e. for use in solution and solid phase chemistry, preferably in a container or package.
• X is carbon, oxygen, a PEG-chain, or a -(CH2) n -CONH- group
• R is hydrogen, phenyl, or substituted phenyl group
• R is hydrogen, phenyl, or substituted phenyl group
• R is hydrogen, C ⁇ -C(, alkyl, C ⁇ -C(, alkoxy, or phenoxy,
• R is hydrogen, Cj-Cs alkyl, Cj-C ⁇ alkoxy, or phenoxy, and n is an integer from 1 to 4.
• Preferred intermediates of the present invention are the following compounds;
• R represents the polymeric support either directly attached to the linker or through a spacer moiety, such as a PEG-chain or a -(CH2) n -CONH- group.
• the starting MAMP amino resin (1 gr; 1.64mmol/g) was pre-swollen in DMF for 10 minutes. To this resin was added a solution of 2,4,5-trichlorophenyl formate (560mg; 2.46mmol, 1.5eq) in 10 mL of DMF. The reaction mixture was agitated at room temperature for 12h. The resin was filtered and washed with DMF (2xl0mL), DCM (2x1 OmL), MeOH (2x1 OmL) and finally dry under vacuum for 1 hour. The resin gives a negative chloranil test, which indicates completion of the reaction.
• the resin was filtered, and washed with dichloromethane (2 1 OmL), methanol (2x1 OmL), and dichloromethane was added to afford the separation of the floating resin from the molecular sieves.
• the resin was washed with lOmL dichloromethane and diethyl ether (2x l0mL) and dried under vacuum for 12h. The resin was then kept under nitrogen at room temperature in the dark for 6 months without any modifcation of its efficiency.
• the heteroaromatic amidine (323 ⁇ mol, 200mol%), the aldehyde (323 ⁇ mol, 200mol%) and the catalyst Sc(OTf)3 (16.2 ⁇ mol, 10mol%) in ImL of a solution of DCM:MeO ⁇ (3: 1) were incubated for 30min.
• the resin isonitrile linker (lOOmg, 163 ⁇ mol. 100mol%) was preswollen for 20 minutes in DCM and the resin filtered.
• the solution of aldehyde, heteroaromatic amidines and catalyst was then added to the resin and the solution was shaken for 2 days at room temperature.
• the resin filtered and washed with DCM(2x3mL), MeOH(2x3mL), 20%DIPEA in DCM(3mL) and DCM(2x3mL).
• a sample of the resin (3- 5mg) was cleaved from the resin with a solution DCM:4M HC1 in dioxane(l: l) for lh at room temperature. The residue was dried under vacuo and analysed by LC-MS, yielding the expected product in high purity (75-99%).
• Resin-bound compound D (60mg, 74 ⁇ mol, 100mol%) was preswollen in DCM for 20 minutes and the resin filtered. A solution of acyl chloride (370 ⁇ mol, 500mol%) and DIPEA (600 ⁇ mol, 800mol%) in ImL of DCM was added to the resin-bound compound D and the reaction mixture was agitated for 20h at room temperature. The resin was filtered and washed with DCM (2x3mL), MeOH (2x3mL), and DCM(2x3mL). A sample of the resin (3-5mg) was cleaved from the resin with a solution of DCM:TFA:water (80: 18:2) for lh at room temperature. The residue was dried under vacuo and analysed by LC-MS, yielding the expected product in high purity (75-99%).
• Resin-bound compound D (60mg, 74 ⁇ mol, 100mol%) was preswollen in DMF for 20 minutes and the resin filtered. A solution of alkyl halides (370 ⁇ mol, 500mol%) and DIPEA (740 ⁇ mol, 1000mol%) in 1.2mL of DMF was added to the resin-bound compound D and the reaction mixture was agitated for 20h at 80°C. The resin was filtered and washed with DMF (2x3mL), DCM (2x3mL), MeOH (2x3mL), and DCM(2x3mL). A sample of the resin (3-5mg) was cleaved from the resin with a solution of DCM:TFA:water (80: 18:2) for lh at room temperature. The residue was dried under vacuo and analysed by LC-MS, yielding the expected product in high purity (75-99%).
• Resin-bound compound D (60mg, 74 ⁇ mol, 100mol%) was preswollen in DCM for 20 minutes and the resin filtered. A solution of sulfonyl chlorides (370 ⁇ mol, 500mol%) and DIPEA (740 ⁇ mol. 1000mol%) in 1.2mL of DCM.Dioxane ( 1 : 1 ) was added to the resin- bound compound D and the reaction mixture was agitated for 20h at 60°C. The resin was filtered and washed with DCM (2x3mL), Dioxane (2x3mL), MeOH (2x3m_L), and DCM(2x3mL).

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• 1999
  • 1999-11-22 SE SE9904222A patent/SE519326C2/sv not_active IP Right Cessation
• 2000
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  • 2000-11-16 AU AU19074/01A patent/AU769893B2/en not_active Ceased
  • 2000-11-16 WO PCT/SE2000/002263 patent/WO2001037983A1/en not_active Application Discontinuation
  • 2000-11-16 JP JP2001539587A patent/JP2003514876A/ja active Pending

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